JP2000178189A - Chlorhexidine preparation, new chlorhexidine salt, solution containing the same salt and its use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a chlorhexidine preparation containing chlorhexidine in a water-soluble form by including a chlorhexidine base and a specific saccharic acid or its lactone at a specific molar ratio and further including an auxiliary at a specific amount. SOLUTION: This chlorhexidine preparation has a form of water-soluble powdery mixture. The chlorhexidine comprises (A) chlorhexidine base and (B) one or more saccharic acids or their lactone selected from a series of compounds comprising gluconic acid or gluconolactone, lactobionic acid (a compound of formula I), D-galactone-γ-lactone (a compound of formula II), L-mannonic acid-γ-lactone (a compound of formula III), D-(-)-gluconic acid-γ- lactone, D-(+)-galactouronic acid (a compound of formula IV) and α-D- heptagluconic acid-γ-lactone at a molar ratio of 1:>=2, preferably 1: (2.05-2.6) and further comprises (C) 0-10 wt.%, preferably <1 wt.%; auxiliary.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a preparation containing chlorhexidine base, which can be converted into an aqueous solution of chlorhexidine salt. Accordingly, the present invention is directed to this solution, and to novel chlorhexidine salts based thereon. The formulations, solutions and salts can be used as bactericides and for their production.

[0002]

2. Description of the Related Art Chemically, 1,1'-hexamethylene-
Chlorhexidine, bis- [5- (4-chlorophenyl) -biguanide], is a strongly basic agent with very low solubility in water. The reaction of chlorhexidine base with a number of acids likewise leads to poorly water-soluble salts. Chlorhexidine base and especially D
(+)-Gluconic acid and its water-soluble salt [CAS-No.
526-95-4] are excellent antibacterial substances for use in the human as well as animal range. It should be emphasized that the toxicity is low and that it is generally compatible with cationic and anionic detergents. Chlorhexidine digluconate is provided as a 20% aqueous solution and is currently the only commercially available water-soluble form of this base. Liquid formulations of chlorhexidine digluconate (CHD-gluconate) are variously modified and used as antimicrobial additives in cosmetics, for disinfecting the skin, for treating wounds, in veterinary medicine as a bactericidal agent, and for surface disinfection. Used for agents.

[0003] Gluconate solutions have overcome the requirements of the European and US Pharmacopeias in their composition and appearance. One of the requirements for purity is 500pp
p-chloroaniline content limited to m. In the reverse reaction of the chlorhexidine base formed from hexamethylene bicyanoguanidine and p-chloroaniline, D (+)-6-lactone gluconate, ie, D (+)
Upon dissolving the base in the intramolecular ester of gluconic acid, p-chloroaniline can be reversibly separated from the solution, whereby the solution becomes more yellow-
Color brown. The decomposition of the chlorhexidine gluconate solution depends on the pH of the solution and especially on the storage temperature. Tests have shown that, under constant storage at 40 ° C., the value of permissible p-chloroaniline is exceeded after about one month (FIG. 1). Long-term stable solutions of CHD-gluconate are not heretofore known. Thus, the use of such solutions in regions with a tropical climate is problematic and has not been satisfactorily solved hitherto. Thus, under adverse tropical conditions, especially when used at high temperatures,
There is a need for a chlorhexidine salt solution that tends to degrade only in small amounts. Unfortunately, almost all salts of cyclohexidine are poorly soluble in water or cannot be used as human or animal fungicides due to the toxicological properties of the anions. What is poorly soluble in water is
For example, chlorhexidine, hydrochloric acid, fluorophosphoric acid,
Bishydroxymethylpropionic acid, acetylsalicylic acid, tartaric acid, 4-hydroxybenzoic acid, 5-sulfosalicylic acid, glyoxalic acid, thioctic acid, L-malic acid,
Sulfanilic acid, nicotinic acid, sarcosine, L (+)-
It is a salt with glutamic acid, citric acid, nitrilotriacetic acid, trimethylolacetic acid, sorbic acid and many other compounds.

Amidosulfuric acid, captopril, levulinic acid,
With N-acetylglycine and S-(-)-pyrrolidinone-5-carboxylic acid, a 20% aqueous solution can indeed be obtained, but this solution is free of crystals upon inoculation or after prolonged standing. Can be issued. Chlorhexidine ascorbate dissolves very well in water, but is photosensitive and less stable than gluconate.

[0005]

Accordingly, it is an object of the present invention to provide storage-stable preparations containing chlorhexidine in water-soluble form. This formulation should be simple to manufacture and convert to an aqueous chlorhexidine salt solution. In addition, the acids required for salt formation should be toxicologically harmless.

[0006]

By the way, a salt of chlorhexidine which is well soluble in water is prepared by adding chlorhexidine base and the following acid or its acid lactone: lactobionic acid (I)
[CAS-No. 96-82-2], D-galactone-
γ-lactone (II) [CAS-No. 2782-07
-2], L-mannonic acid-γ-lactone (III) [C
AS-No. 22430-23-5], D-(-)-gulonic acid-γ-lactone (IV) [CAS-No. 632
2-07-2], D-(+)-galacturonic acid (V)
[CAS-No. 91510-62-2] and α-D
-Heptagluconic acid-γ-lactone (VI) [CAS-
No. 60046-25-5]

[0007]

Embedded image

It has been found that they can be prepared by reacting

Furthermore, a cyclohexidine base and a compound of the formula (I)
The sugar acid or its lactone and the powdered mixture with gluconic acid or gluconolactone selected according to (VI) are substantially more soluble than the readily available aqueous solution by dissolving the chlorhexidine salt in water. Storage stable. Accordingly, the subject of the present invention is a chlorhexidine preparation according to claim 1.

Another object is that the chlorhexidine salt is chlorhexidine and lactobionic acid (I), D-galactonic acid (II '), L-mannonic acid (III'), D-(-).
-Gulonic acid (IV '), D-(+)-galacturonic acid (V) and α-D-heptagluconic acid (VI'). It is an aqueous solution of a chlorhexidine salt having a content of 01% by mass. The concentration of chlorhexidine salt is
It is generally in the range from 0.01 to 30% by weight, in particular from 1 to 20% by weight.

Further, the present invention relates to lactobionic acid (I), D-(+)-galacturonic acid (V), D-galactonic acid (II '), L-mannonic acid (III'),
Gulonic acid (IV) and α-D-heptagluconic acid (V
A novel water-soluble chlorhexidine salt, characterized by the acid anion of the sugar acid from the series I ').

Storage tests relating to the salt solutions according to the invention show that their storage stability is comparable to that of chlorhexidine gluconate solution. Long term p
-The problem of chloroaniline separation cannot be solved by introducing new anions. However, surprisingly, the powdered formulations according to the invention are very storage-stable-see FIGS. 1 and 2.

FIG. 1 shows the time-dependent formation of p-chloroaniline (p-CA) in a 20% by weight aqueous chlorhexidine digluconate solution and the corresponding powdery mixture.

FIG. 2 shows the formation of p-chloroaniline from a solution of chlorhexidine di-D-(-)-heptagluconate and from a powder mixture containing chlorhexidine and glucoheptonic-lacton according to the invention. 2 shows the formation of p-chloroaniline.

By the way, p-chloroaniline-poor chlorhexidine digluconate solution or sugar acid anion based on formulas (I) to (IV), having a content of at least 0.01% by weight, preferably 20% by weight A solution of each salt having the following formula is used to form a finely divided mixture of chlorhexidine base and gluconic acid or gluconolactone as well as a sugar acid or its lactones (I) to (VI):
Acid / lactone 1: 2 to 1:> 2, especially 1: 2.0
It was found to be prepared by dissolving by adding the required amount of water in a ratio of 5-2.6.
With the use of a formulation having the sugar acid (I), (V) or (VI), the dissolution is carried out for about 20 minutes at room temperature with occasional shaking and the sugar lactone (II), (III) or ( It is carried out by using warm water with the use of a preparation having IV).

The powder formulation according to the invention is stable on storage even at high temperatures for a long period of time and does not separate p-chloroaniline-see FIGS. 1 and 2. In order to avoid coagulation of the formulation, the free water content should be advantageously less than 0.05%.

The mixture consisting of chlorhexidine base and sugar acid or sugar acid lactone is mixed in a suitable apparatus, for example in a tumble mixer (Taumelmischer), dry mixer.
Obtained by close homogenization at (Draismischer) and subsequently crushed. Alternatively, it is also possible to feed both components separately at a calculated ratio to the milling device.
In the present specification, a spiral jet mill (Spiralstrahlmuehle) is suitably exemplified. Also, the base and acid / lactone are ground separately, and subsequently stoichiometrically,
Appropriately adjusted and can be added to the container. The latter variant is advantageously suitable for filling so-called potion packs, which are consumed at one time and thus less than homogenous, since they dissolve in water.
This is because the appropriate ratio of acid / lactone: base is automatically adjusted. Optionally, the formulation contains 0-10% by weight,
Advantageously, less than 1% by weight of auxiliaries, such as fragrances, dyes, other fungicides and surfactants, may be added.

For rapid dissolution, it is advantageous to use the components used in as fine a particle size as possible.
Advantageously, a particle size of d ₅₀ <50 μm is recommended.

From aqueous solutions prepared from chlorhexidine base and sugar acids or sugar lactones, it is also possible to obtain the chlorhexidine salt in crystalline form. For the preparation of solid salts, the solution is advantageously evaporated under reduced pressure; after leaving the highly viscous substance on the desiccant for a long time, the material may become brittle and may be ground to a powder. According to an alternative embodiment, the concentrated aqueous solution of the chlorhexidine salt is subjected to vacuum sublimation at low temperature (eg freeze-drying at -60 ° C). By such a method, a crystalline salt is obtained which directly dissolves in water spontaneously.

The preparations, solutions and chlorhexidine salts according to the invention can be used as fungicides or for their production.

[0021]

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The preparation of the salt solution is carried out according to the components (I) to (V
I) and the calculated amounts of water and chlorhexidine base are added together.

A) by reacting the sugar acids of (I), (V) and (VI) with chlorhexidine base
Provision for producing a chlorhexidine salt aqueous solution by mass.

(I) 35.8 g or (V) 21.2 g
Or 21 g (VI) of chlorhexidine base 25.
0 g together with 243 g or 185 g or 180 of water
g and the resulting milky suspension is added at room temperature for about 10
Stir for ~ 15 min and adjust the pH to 5-6 by adding (I), (V) or (VI) separately as needed. The resulting clear solutions each contain 20% by weight of the corresponding chlorhexidine salt.

B) Rules for producing a 20% by mass aqueous chlorhexidine salt solution by reacting the lactone lactones of (II), (III) and (IV) with a chlorhexidine base.

(II) or (III), (IV) 1
9.5 g are added to 171 g of water together with 25.0 g of chlorhexidine base and the resulting suspension is warmed at 60-80 ° C. for about 5-10 minutes. If necessary, (II), (II
By adding I) and (VI) separately, the pH was adjusted to 5 to 5.
Adjust to 6. A clear solution of 20% by weight of the corresponding chlorhexidine salt is obtained.

2. Preparation of chlorhexidine salt a) 10.0 g of chlorhexidine base and 8.3 g of D-heptagluconic acid-γ-lactone are dissolved in 35 ml of water. The solution is evaporated in a vacuum to dry. After standing over P ₄ O _10, salts of hepta chlorhexidine gluconate, as a colorless crystalline substance having a melting range of 72-76 ° C..

B) In a similar manner, chlorhexidine (C
H) Another salt of chlorhexidine heptagluconate is obtained as a salt, the melting points of which are as follows: CH-lactobionate 100-115 ° C. CH-galacturonate 118-125 ° C. CH-galactonate 140-145 ° C.

[Brief description of the drawings]

FIG. 1: p-chloroaniline (p-chloroaniline) in 20% by weight aqueous chlorhexidine digluconate solution or solid mixture
FIG. 4 is a diagram showing the change over time in the concentration of CA).

FIG. 2 is a diagram showing the change over time of p-chloroaniline in a solution of chlorhexidine di-D-(−)-heptagluconate and in a powdery mixture containing glucohepton-lactone.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification FI FI Theme Court ゛ (Reference) (72) Inventor Fleethelm Merz Nielstein Langgasse 25, Germany (72) Inventor Judith N. Järgensen Denmark Hillered Esterwang 94 (72) Inventor Martin Trager, Germany Gernhausen sur Strasse 1a

Claims (4)

[Claims] 1. A chlorhexidine formulation in the form of a water-soluble, powdery mixture, comprising chlorhexidine base, gluconic acid or gluconolactone, lactobionic acid (I), D
-Galactone-γ-lactone (II), L-mannonic acid-γ-lactone (III), D-(-)-gluconic acid-
one or more sugar acids or lactones thereof from the series γ-lactone (IV), D-(+)-galacturonic acid (V) and α-D-heptagluconic acid-γ-lactone (VI); A chlorhexidine preparation comprising 0 to 10% by mass of an auxiliary agent, wherein the molar ratio of the chlorhexidine base to the sugar acid or its lactone is 1: 2 or more. 2. The preparation according to claim 1, wherein the molar ratio of chlorhexidine base to sugar acid or lactone is 1: 2.05 to 2.6, and the content of the auxiliary is less than 1% by mass. 3. An aqueous solution of a chlorhexidine salt having a content of at least 0.01% by mass, wherein the chlorhexidine salt comprises lactobionic acid (I), D-galactone-
γ-lactone (II), L-mannonic acid-γ-lactone (III), D-(−)-gulonic acid-γ-lactone (I
V), D-(+)-galacturonic acid (V) and α-
An aqueous solution of a chlorhexidine salt, which is selected from the series of salts of D-heptagluconic acid-γ-lactone (VI). 4. Lactobionic acid (I), D-galactone-γ-lactone (II), L-mannonic acid-γ-lactone (III), D-(−)-gulonic acid-γ-lactone (IV), D-(+)-galacturonic acid (V), D-
Galactonic acid (II '), L-mannonic acid (II
I '), a water-soluble chlorhexidine salt, characterized in that it is an acid anion of a sugar acid from the series of gulonic acid (IV) and α-D-heptagluconic acid (VI').